Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>CS(C)=O.O>[C:15]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccccc1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Nc1ccccc1-c1ccccc1
Reaction time: 16 h
Yield: 55.9 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzonitrile (690 mg, 4.13 mmol, 1 equiv) and 2-aminobiphenyl (700 mg, 4.13 mmol, 1 equiv) in anhydrous DMSO (20 mL) at room temperature was added potassium tert-butoxide (930 mg, 8.26 mmol, 2 equiv). After 16 h, the reaction mixture was diluted with water, and extracted into EtOAc (×3). The EtOAc extractions were combined, washed with water (×5), brine, dried (Na2SO4), filtered and concentrated. The crude residue was dry-loaded onto silica gel and purified by flash column chromatography (CH2Cl2/Hex/EtOAc, 10:10:1) to afford 2-([1,1′-biphenyl]-2-ylamino)-5-nitrobenzonitrile as an orange solid (728 mg, 56%): δH (CDCl3, 400 MHz) 8.31 (d, J=2.4, 1H, Ar), 8.10 (dd, J=9.6, 2.4, 1H, Ar), 7.50-7.24 (m, 9H, Ar), 6.92 (d, J=9.6, 1H, Ar), 6.79 (s, 1H, NH); δC (CDCl3, 100 MHz) 152.2, 138.5, 137.9, 137.5, 134.4, 131.6, 129.7, 129.5, 128.9, 128.8, 128.6, 128.2, 127.6, 125.4, 115.2, 112.5, 96.7), which was subsequently hydrolyzed (1.17 mmol scale) with NaOH (140 mg, 3.52 mmol, 2 equiv) in a 1:1:1 mixture of dioxane/EtOH/H2O (12 mL) at reflux for 48 h. The reaction mixture was concentrated to dryness, and then partitioned between Et2O and H2O to remove neutral organics. The aqueous layer was acidified with 1M HCl, and then extracted with EtOAc (×3). The EtOAc extractions were combined, washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was dry-loaded onto silica gel and purified by flash column chromatography (CH2Cl2/MeOH/AcOH, 92:7:1) to deliver the title compound 2-([1,1′-biphenyl]-2-ylamino)-5-nitrobenzoic acid (SF-3-103B) as an orange solid (293 mg, 75%): δH (CDCl3+MeOH-d4, 400 MHz) 10.01 (s, 1H, OH), 8.80 (d, J=2.4, 1H, NH), 7.98 (dd, J=9.6, 2.4, 1H, Ar), 7.43-7.17 (m, 11H, Ar), 6.82 (d, J=9.6, 1H, Ar); δC (CDCl3, 100 MHz) 169.2, 153.2, 138.3, 138.2, 137.0, 135.4, 131.4, 129.5, 129.1, 128.8, 128.5, 128.4, 127.5, 126.9, 126.0, 113.0, 110.2.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].O.[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:25][O:12][C:11](=[O:13])[C@@H:2]([NH:1][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:3][C:4]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To Cbz-Asp(O-tert-Bu)-OH.H2O (5.00 g, 14.6 mmol) and K2CO3 (4.05 g, 2.0 eq) were added DMF (100 mL) and MeI (2.74 mL, 3 eq), which was then stirred for 2-3 h at room temperature. The solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate (100 mL×2), washed with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (30% ethyl acetate/hexane) to give (S)-2-benzyloxycarbonylamino-succinic acid 4-tert-butyl ester 1-methyl ester in a stoichiometric yield. This compound was dissolved in MeOH (100 mL), c-HCl (1.1 mL, 1.0 eq) was added, and subjected to debenzyloxycarbonylation (Pd/C) for 40 min under hydrogen balloon, whereby giving 3.28 g (96%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]#[C:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][CH2:12]1.[CH:25]1[C:30]([O:31][C:32](Cl)=[O:33])=[CH:29][CH:28]=[C:27]([Cl:35])[CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:35][C:27]1[CH:28]=[CH:29][C:30]([O:31][C:32]([N:9]([CH2:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]#[C:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:16]2)[CH3:8])=[O:33])=[CH:25][CH:26]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CNC[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 45 h

Procedure:
A solution of 7.70 g (corresponds to 9.63 mmol) of crude trans-methanesulfonic acid 3-(4-methylaminomethyl-cyclohexyl)-prop-2-ynyl ester trifluoro-acetate in 60 ml methylenechloride was treated at 0° C. with 1.61 ml (11.56 mmol) 4-chlorophenylchloroformate and then during 3 minutes with 8.25 ml (48.17 mmol; 5 equivalents) of Huenig's base. The reaction was stirred 45 hours at room temperature and extracted with aqueous 10% KHSO4/ether (3×). The organic phases were washed with aqueous 10% NaCl and dried over sodium sulfate to yield 5.3 g of crude trans-methanesulfonic acid 3-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexyl)-prop-2-ynyl ester as dark brown oil, MS: 414 (MH+, 1Cl).
Reaction SMILES: Cl.C[O:3][C:4](=[O:7])[CH2:5]N.C([N:10]([CH:14](C)C)[CH:11]([CH3:13])C)C.[CH2:17](Cl)Cl>>[N:10]1[CH:11]=[CH:13][CH:17]=[C:5]([C:4]([OH:3])=[O:7])[CH:14]=1
Reactant: COC(=O)CN
Reactant: CCN(C(C)C)C(C)C
Reactant: ClCCl
Agent: Cl
Product: O=C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride starting material of Example 1 (12.81 g=0.0345 mole) was dissolved in 100 ml CH2Cl2. To this solution was added 4.68 g (0.0373 mol) of glycine methyl ester hydrochloride. This mixture was cooled in an ice bath before adding 10 ml of ethyldiisopropylamine (EDPA)(0.0574 mole) by pipet. The ice bath was removed, and the reaction stirred overnight at room temperature. 19F NMR showed the reaction was incomplete. An additional 3 ml of EDPA (0.0172 mol) was added. After 1/2 hour a gas chromatographic assay showed complete reaction. It was washed with dilute HCl and extracted with CH2Cl2. The CH2Cl2 layer was dried with MgSO4, filtered and concentrated to 14.2 g orange oily solid. Two grams were chromatotroned (20% EtOAc/cyclohexane) and then recyrstallized to give 1.2 g of 3-pyridinecarboxylic acid, 6-(difluoromethyl)-5-[[(2-methoxy-2-oxoethyl)amino]carbonyl]-4-(2-methylpropyl)-2-(trifluoromethyl)-, methyl ester as a white solid. m.p. 126°-129° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:16](=[O:27])[CH2:17][NH:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:7]2[CH:13]([CH3:15])[CH3:14].CCO.C(N(CC)CC)C.[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>[Pd].C(OCC)C>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[CH:13]([CH:7]1[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][C:9]=2[CH3:12])[CH2:4][CH2:5][N:6]1[C:16](=[O:27])[CH2:17][NH:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:15])[CH3:14]
Reactant: Cc1ccc(Br)c2c1C(C(C)C)N(C(=O)CNCC1(O)CCCCC1)CC2
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOCC
Product: Cc1cccc2c1C(C(C)C)N(C(=O)CNCC1(O)CCCCC1)CC2
Reaction time: 6 h
Yield: 57.6 %

Procedure:
A mixture of 1-({[2-(5-bromo-1-isopropyl-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol (0.14 g), EtOH (10 mL), triethylamine (0.05 mL), and 10% palladium-supported carbon (10 mg) was stirred under a hydrogen atmosphere for 6 hours. The reaction liquid was filtered and the solvent was evaporated. A 1 M NaOH aqueous solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-MeOH). The resulting residue was dissolved in 2-propanol (0.8 mL). To the reaction liquid were added oxalic acid (23 mg) and diethyl ether (5 mL) and the precipitated solid was collected by filtration and dried to obtain 1-({[2-(1-isopropyl-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol oxalate (0.066 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Sulfur trioxide pyridine complex (800 mg, 5.0 mmol) was added to a solution of 3-[5-methyl-3-(1-naphthalenylsulfonyloxy)phenoxy]propanol (600 mg, 1.6 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (60 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (540 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 9.76 (s, 1H), 8.80 (d, J=8.6 Hz, 1H), 8.14 (d, J=7.7 Hz, 2H), 7.99 (d, J=8.1 Hz, 1H), 7.78 (t, J=8.1 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.35 (s, 1H), 6.20 (s, 1H), 4.02 (t, J=6.1 Hz, 2H), 2.76 (t, J=6.1 Hz, 2H), 2.15 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: OCC1CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.8 %

Procedure:
To a solution of cyclobutylmethanol (25 g, 290 mmol) in CH2Cl2 (200 mL) and pyridine (100 mL) was added 4-(dimethylamino)pyridine (1.8 g, 14.5 mmol) followed by p-toluenesulfonyl chloride (55.3 g, 290 mmol). The mixture was allowed to stir at ambient temperature for 20 hours then quenched with 5% aqueous HCl (30 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (50.8 g, 211 mmol, 73% yield). MS (DCI/NH3) m/z 258 (M+NH4)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([OH:13])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:30]=[C:29]([Cl:31])[C:28]([I:32])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:31][C:29]1[C:28]([I:32])=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([NH:20][C:11](=[O:13])[CH2:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[CH:30]=1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c(Cl)cc1NC(=O)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 2-(phenylsulfonyl) acetic acid (Lancaster Synthesis Ltd., 0.771 mg, 3.85 mmol) in dichloromethane (50 mL) was added oxalyl chloride (4.17 mL, 4.17 mmol) and few drops of DMF. The reaction mixture was stirred 2 hours at room temperature. To a solution of methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (1 g, 3.21 mmol) and triethylamine (1.074 mL, 7.70 mmol) in dichloromethane (50 mL) at RT was added dropwise the acid chloride prepared above. The reaction mixture was stirred at room temperature overnight then quenched with aqueous solution of NaHCO3. The organic layer was and washed with saturated NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound methyl 4-chloro-5-iodo-2-(2-(phenylsulfonyl)acetamido)benzoate (1.1 g, 2.228 mmol, 69.4% yield) as pale yellow powder. LCMS: (M+H)+=494; Rt=3.58 min.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:6][CH:5]([OH:7])[C:4]1([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.Cl[C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([S:30][CH3:31])[N:21]=1>C1COCC1.CN(C=O)C>[CH3:8][C:4]1([CH3:9])[C@H:3]([NH:2][C:24]2[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:20][N:21]=[C:22]([S:30][CH3:31])[N:23]=2)[CH2:6][C@@H:5]1[OH:7]
Reactant: CC1(C)C(N)CC1O
Reactant: CSc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(F)(F)F)c(N[C@@H]2C[C@H](O)C2(C)C)n1
Temperature: 25 °C

Procedure:
In a round-bottomed flask, 3-amino-2,2-dimethylcyclobutanol hydrochloride (peak 1, obtained above) (1.0 equiv.) and DIEA (1.3 equiv.) were combined in THF (1.0 M) and DMF (1.0 M). To this solution was added 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (1.0 equiv.) at 0° C. The mixture was allowed to warm to room temperature over 2 h; LCMS showed the desired product. Ethyl acetate was added and the organic phase was separated and dried over sodium sulfate. The organic phase was filtered and concentrated to a residue. The dried residue was purified by silica gel chromatography (Biotage column, 0-50% hexane in ethyl acetate; 340 g SNAP column). Concentration of the desired fractions afforded the title compound. The stereochemistry was determined as described for other intermediates described herein, by X-ray crystallography. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.22 (d, J=0.63 Hz, 1H) 5.21 (br. s., 1H) 4.08-4.23 (m, 1H) 3.78-3.91 (m, 1H) 2.80 (dt, J=11.66, 7.41 Hz, 1H) 2.52-2.57 (m, 3H) 1.79 (ddd, J=11.66, 9.46, 7.88 Hz, 1H) 1.67 (d, J=6.31 Hz, 1H) 1.24-1.32 (m, 3H) 0.97-1.06 (m, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[CH3:25].FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1Nc1nc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)ccc1Nc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.6 %

Procedure:
In methylene chloride (10 ml) was dissolved tert-butyl (4-(2-benzoxazolyl)amino-3-methylphenyl)acetate (1.17 g, 3.46 mmol). To the resulting solution was added trifluoroacetic acid (10 ml). The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was poured in ice water, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/methanol (60:1 to 50:1, v/v) eluate fractions, (4-(2-benzoxazolyl)amino-3-methylphenyl)acetic acid (924 mg, 95%) was obtained as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:30]([C:27]3[CH:28]=[N:29][C:24]([Cl:23])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[N:9]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CN)o1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)c4ccc(Cl)nc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=429.1 (M+H+), was prepared in accordance with the general method of example 58 from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 6-chloro-pyridine-3-sulfonylchloride.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:17])([F:16])[CH2:8][CH2:9][O:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[C:18](=O)(O)[O-:19].[Na+]>CN(C)C=O>[F:17][C:7]([F:6])([F:16])[CH2:8][CH2:9][O:10][C:11]1[S:12][C:13]([CH:18]=[O:19])=[CH:14][CH:15]=1
Reactant: O=C([O-])O
Reactant: FC(F)(F)CCOc1cccs1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCC(F)(F)F)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
To 8 mL dimethylformamide at room temperature was added phosphorous oxychloride (4.0 mL, 43.33 mmol) dropwise. After stirring for 10 minutes at room temperature, 2-(3,3,3-trifluoropropoxyl)thiophene (1.70 g, 8.67 mmol) as a solution in 8 mL dimethylformamide. The resulting solution was heated to 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was poured into 100 mL of ice-water and stirred vigorously for 5 minutes. Sodium bicarbonate (11 g) was added carefully and the mixture stirred until homogeneous. Organics were extracted with ether (3×100 mL), washed with water (3×50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (0-20% ethyl acetate in hexanes) to give 5-(3,3,3-trifluoropropoxyl)thiophene-2-carbaldehyde (761 mg, 39%) as an off-white solid. Used without further characterization.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30].CO.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.O1CCCC1>[CH3:26][C:25]1[C:20]([C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]4[N:5]([CH:27]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:3]=4)[CH:6]=3)[CH:12]=2)=[O:19])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4ncccc4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 41.2 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (129 mg, 0.359 mmol) in N,N-dimethylacetamide (6 mL) was added propionylchloride (34.3 μL, 0.395 mmol), and the mixture was stirred at room temperature for 22 hr. Methanol, tetrahydrofuran and aqueous sodium carbonate solution were added to the reaction mixture, and the mixture was stirred at 60° C. for 22 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (61.4 mg, 41%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[NH:19][CH2:18][CH2:17][C:16]3[C:11]2=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)=[CH:5][C:4]=1[O:24][CH3:25].Cl.I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([S:46][C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[C:34]#[N:35]>>[CH3:45][O:44][C:38]1[CH:37]=[C:36]([C:33]([S:46][C:47]2[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=2)([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:19]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)[CH:10]2[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:24][CH3:25])[CH:5]=2)[C:34]#[N:35])[CH:41]=[CH:40][C:39]=1[O:42][CH3:43]
Reactant: COc1ccc(C(C#N)(CCCCCI)Sc2ccc(C)cc2)cc1OC
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CCCCCC(C#N)(Sc2ccc(C)cc2)c2ccc(OC)c(OC)c2)cc1OC
Yield: 61.1 %

Procedure:
The procedure of Example 49 is repeated using 0.345 g of tetrahydropapaverine hydrochloride and 0.30 g of α-(5-iodopentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile. This affords 0.263 g of the desired product as a yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3[C:18]4[NH:22][C:21](=[O:23])[NH:20][C:19]=4[CH:24]=[CH:25][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:41])[CH3:40])[CH:35]=[CH:36][CH:37]=1>CS(C)=O.C(OCC)(=O)C>[O:23]=[C:21]1[NH:22][C:18]2=[C:17]3[C:16](=[CH:25][CH:24]=[C:19]2[NH:20]1)[O:15][CH2:14][CH:13]([CH2:12][NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:41])[CH3:40])[CH:35]=[CH:36][CH:37]=1)[O:26]3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(=O)[nH]c4c3O2)cc1
Reactant: CC(=O)Nc1cccc(OCCCN)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)Nc1cccc(OCCCNCC2COc3ccc4[nH]c(=O)[nH]c4c3O2)c1
Temperature: 95 °C

Procedure:
A mixture of 0.60 g (1.6 mmole) of (8R)-1,3,7,8-tetrahydro-8-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-2H-[1,4]dioxino[2,3-e]benzimidazol-2-one and 1.6 g (8.0 mmole) of N-[3-(3-amino-propoxy)phenyl]-acetamide in 30 mL of DMSO was heated at 90-100° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 500 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform as eluant and the product fractions evaporated to give the free base of the title compound. This was recrystallized from ethanol with the addition of fumaric acid to give 0.19 g of the (S)-enantiomer of the title compound as a white solid fumarate, three-quarter hydrate, m.p. 125° C. (d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]3[C:15]2=[O:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCCN)cc1OC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: COc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1OC

Procedure:
6.4 g of 3-(3,4-dimethoxyphenyl)-propylamine (0.03 moles) was refluxed with 5.47 g of phthalic anhydride (0.037 moles) in 70 ml of acetic acid for 2.5 hours. The solvent was then removed in the rotary evaporator. Recrystallization of the residue from 150 ml of ether gave 4.0 g of a first crop, m.p. 82°-85° and 7.0 g of a second crop, m.p. 81°-83°.